JP2023141229A - Pharmaceutical composition used for treatment of hyperphosphatemia - Google Patents
Pharmaceutical composition used for treatment of hyperphosphatemia Download PDFInfo
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Abstract
Description
本発明は、高リン血症の治療に用いられる医薬用組成物に関する。 The present invention relates to pharmaceutical compositions used for the treatment of hyperphosphatemia.
高リン血症とは、血中の無機リン濃度が4.5mg/dL(1.46mmol/L)を上回る状態をいう。高リン血症は、進行した腎機能不全(GFR<30mL/分)、糖尿病性ケトアシドーシス、外傷によらない横紋筋融解症、及び腫瘍崩壊症候群などで最もよく見られる。大半の患者は無症状であるが、高リン血症が進行すると、リン酸とカルシウムが結合して生成するリン酸カルシウムが骨以外の組織に沈着する異所性石灰化や、活性型ビタミンDの産生低下により副甲状腺ホルモンが過剰に分泌される二次性副甲状腺機能亢進症などを引き起こす。特に、異所性石灰化は、血管で生じると動脈硬化や心筋梗塞の原因となるため、高リン血症は早期の治療が望まれる。 Hyperphosphatemia refers to a state in which the concentration of inorganic phosphorus in the blood exceeds 4.5 mg/dL (1.46 mmol/L). Hyperphosphatemia is most commonly seen in advanced renal insufficiency (GFR <30 mL/min), diabetic ketoacidosis, non-traumatic rhabdomyolysis, and tumor lysis syndrome. Most patients are asymptomatic, but as hyperphosphatemia progresses, ectopic calcification occurs, in which calcium phosphate, which is formed by the combination of phosphate and calcium, is deposited in tissues other than bones, and the production of active vitamin D. This decrease causes secondary hyperparathyroidism, where parathyroid hormone is secreted in excess. In particular, if ectopic calcification occurs in blood vessels, it can cause arteriosclerosis and myocardial infarction, so early treatment of hyperphosphatemia is desired.
現状の高リン血症治療では、リンの摂取制限、リン吸着薬の服用、食塩水による利尿、血液透析などが行われている。リン吸着薬としては、以前は水酸化アルミニウムが使用されていたが、水酸化アルミニウム製剤の長期使用が透析患者におけるアルミニウムの体内蓄積を招き、アルミニウム骨症やアルミニウム脳症というような深刻な副作用が見られた。このため、水酸化アルミニウム製剤は、1992年より透析患者では禁忌となった。その後、炭酸カルシウム剤が高リン血症治療薬として正式に認可された。しかし、炭酸カルシウム剤の服用により高カルシウム血症が高頻度に発症しており、さらに副甲状腺の過剰抑制、無形成骨や軟部組織の石灰化や血管石灰化の問題が指摘されている。このため、炭酸カルシウム製剤の大量使用は避ける方向にあり、炭酸ランタンや塩酸セベラマーなどの非アルミニウム・非カルシウム性リン低下薬との併用が基本となっている。 Current treatments for hyperphosphatemia include restricting phosphorus intake, taking phosphorus-adsorbing drugs, diuresis with saline, and hemodialysis. Aluminum hydroxide was previously used as a phosphorus adsorbent, but long-term use of aluminum hydroxide preparations leads to accumulation of aluminum in the body of dialysis patients, and serious side effects such as aluminum osteopathy and aluminum encephalopathy have been observed. It was done. For this reason, aluminum hydroxide preparations have been contraindicated in dialysis patients since 1992. Later, calcium carbonate was officially approved as a hyperphosphatemia treatment. However, hypercalcemia frequently occurs when taking calcium carbonate agents, and problems have also been pointed out, including excessive suppression of the parathyroid glands, calcification of aplastic bone and soft tissues, and calcification of blood vessels. For this reason, large amounts of calcium carbonate preparations are being avoided, and their use in combination with non-aluminum, non-calcium phosphorus-lowering drugs such as lanthanum carbonate and sevelamer hydrochloride is the norm.
細胞内外での無機リン濃度の恒常性は、リン酸取り込みトランスポーターSLC20A2とリン酸排出トランスポーターXPR1のリンクにより維持されている(図1)。SLC20A2により細胞内に取り込まれたリン酸は、ATPに変換されるが、ATPは、フィチン酸(myo-イノシトール-1,2,3,4,5,6リン酸、IP6)をリン酸化する酵素であるIP6キナーゼ(IP6K)を活性化する。IP6Kは、細胞内のイノシトール6リン酸(IP6)をイノシトールピロリン酸(IP7)へと変換する。IP7は、XPR1に作用して、細胞内のリン酸を排出する。SLC20A2とXPR1はリンクしており、SLC20A2を過剰発現させると、リン酸の取り込みが増大すると同時に、XPR1を介したリン酸の排出が起こる。このようにして、細胞内外のリン酸濃度のバランスが保たれ、血中無機リンの正常値が維持されている。高リン血症の原因の一つに、SLC20A2とXPR1の機能不全が挙げられる。実際に、異所性石灰化の一種である特発性基底核石灰化症は、大脳基底核等に石灰化を伴う原因不明の疾患であるが、家族性特発性基底核石灰化症の原因遺伝子として、SL20A2遺伝子、XPR1遺伝子を含む数種の遺伝子が報告されている。 Homeostasis of inorganic phosphorus concentration inside and outside cells is maintained by a link between the phosphate uptake transporter SLC20A2 and the phosphate efflux transporter XPR1 (Figure 1). Phosphate taken into cells by SLC20A2 is converted to ATP, and ATP is an enzyme that phosphorylates phytic acid (myo-inositol-1,2,3,4,5,6 phosphate, IP6). Activates IP6 kinase (IP6K). IP6K converts intracellular inositol hexaphosphate (IP6) to inositol pyrophosphate (IP7). IP7 acts on XPR1 to excrete intracellular phosphate. SLC20A2 and XPR1 are linked, and overexpression of SLC20A2 increases phosphate uptake while simultaneously causing phosphate excretion via XPR1. In this way, the balance of phosphate concentration inside and outside the cells is maintained, and normal levels of inorganic phosphorus in the blood are maintained. One of the causes of hyperphosphatemia is dysfunction of SLC20A2 and XPR1. In fact, idiopathic basal ganglia calcification, a type of ectopic calcification, is a disease of unknown cause that involves calcification in the basal ganglia, etc., but the gene that causes familial idiopathic basal ganglia calcification Several genes have been reported as such, including the SL20A2 gene and the XPR1 gene.
IP6K阻害剤であるN6-(p-ニトロベンジル)プリン(TNP)によってIP7の生成が抑えられ、血中のリン濃度が減少することが報告されている(非特許文献1)。更に、TNPより強力なIP6K阻害剤であるSCO-006も報告されている(非特許文献2)。これらの知見から、IP6Kは高リン血症治療薬の標的になると期待される。また、IP6は、リン酸カルシウムの蓄積による石灰化を抑制できることが報告されている(非特許文献3及び4)。 It has been reported that N6-(p-nitrobenzyl)purine (TNP), an IP6K inhibitor, suppresses the production of IP7 and reduces blood phosphorus concentration (Non-Patent Document 1). Furthermore, SCO-006, which is a more potent IP6K inhibitor than TNP, has also been reported (Non-Patent Document 2). Based on these findings, IP6K is expected to become a target for hyperphosphatemia therapeutics. Furthermore, it has been reported that IP6 can suppress calcification due to accumulation of calcium phosphate (Non-Patent Documents 3 and 4).
一方で、IP6は、抗がん作用、免疫力上昇作用、腎結石形成抑制作用、コレステロール低下作用、冠動脈疾患や糖尿病の発症リスク軽減などの多彩な活性を持つことが知られている(非特許文献5)。IP6はこのように多くの有用な効果を奏するが、6個のリン酸基に由来する多くの負電荷を持つために細胞膜を通りづらく、細胞のIP6取り込み量には限界がある。また、IP6は、金属とキレートする性質を持ち、体内のミネラルの吸収を妨げることから、大量摂取による副作用が指摘されている。そこで、IP6の細胞内への取り込み量を改善したプロドラッグ体として、フィチン酸エステル誘導体(特許文献1)が開発されている。当該フィチン酸エステル誘導体は、IP6のリン酸基がエステル化によって保護されており、これにより脂溶性が向上して細胞への取り込み効率が改善されている。細胞内に取り込まれたフィチン酸エステル誘導体は、細胞内の酵素による加水分解反応によって、IP6となる。 On the other hand, IP6 is known to have a variety of activities, including anti-cancer effects, immune-boosting effects, kidney stone formation-inhibiting effects, cholesterol-lowering effects, and reducing the risk of developing coronary artery disease and diabetes (non-patented). Reference 5). IP6 has many useful effects as described above, but because it has many negative charges derived from six phosphate groups, it has difficulty passing through cell membranes, and there is a limit to the amount of IP6 that can be taken up by cells. In addition, IP6 has the property of chelating with metals and hinders the absorption of minerals in the body, so side effects have been pointed out when ingested in large amounts. Therefore, phytic acid ester derivatives (Patent Document 1) have been developed as prodrugs that improve the amount of IP6 taken into cells. In the phytic acid ester derivative, the phosphate group of IP6 is protected by esterification, which improves the fat solubility and improves the efficiency of uptake into cells. The phytate derivative taken into cells becomes IP6 through a hydrolysis reaction by intracellular enzymes.
高リン血症の治療に用いられる治療薬の多くは、リン酸との結合能力が高い薬剤を有効成分とするリン吸着薬である。これらのリン吸着薬は消化管からのリンの吸収阻害を目的としているものであり、体内でのリン酸量自体を低減させることはできない。加えて、リン吸着薬の多くは、量が多いため服用しにくいことや、便秘や腹部膨満感など消化器系副作用が多いなどの問題点がある。 Many of the therapeutic drugs used to treat hyperphosphatemia are phosphorus adsorbents whose active ingredients are drugs that have a high ability to bind phosphoric acid. These phosphorus adsorbents are intended to inhibit absorption of phosphorus from the gastrointestinal tract, and cannot reduce the amount of phosphoric acid in the body itself. In addition, many phosphorus adsorbing drugs have problems such as being difficult to take due to their large doses and having many gastrointestinal side effects such as constipation and abdominal bloating.
本発明は、体内でのリン酸量を低減させることが可能な高リン血症治療に適した医薬用組成物を提供することを目的とする。 An object of the present invention is to provide a pharmaceutical composition suitable for treating hyperphosphatemia that can reduce the amount of phosphate in the body.
本発明者らは、上記課題を解決すべく鋭意研究した結果、IP6のリン酸基の少なくとも一部がエステル化によって保護されたフィチン酸エステル誘導体をマウスに経口投与した場合に、血中無機リン値を強力に低下させることを見出し、本発明を完成させた。 As a result of intensive research aimed at solving the above problems, the present inventors found that when a phytate ester derivative in which at least a portion of the phosphate group of IP6 was protected by esterification was orally administered to mice, blood inorganic phosphorus The present invention was completed based on the discovery that the value can be strongly reduced.
[1] 本発明の第一の態様に係る医薬用組成物は、下記一般式(1)[式中、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12は、それぞれ独立して、水素原子、-Z1-O-C(=O)-R21、又は、-Z1-S-C(=O)-R21であり;前記Z1は、-CH2-、-CH2-CH2-、又は、-CH2-C4H6-であり;Z1中の1又は複数の水素原子は、置換基で置換されていてもよく;前記R21は、置換基を有していてもよい炭素数1~6のアルキル基、又は、置換基を有していてもよいアリール基であり:一分子中に複数あるZ1及びR21は、いずれも互いに同種の基であってもよく、異種の基であってもよい;ただし、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の全てが水素原子である化合物を除く]
で表される化合物、若しくはその薬理学的に許容される塩、又はそれらの溶媒和物を有効成分とし、高リン血症の治療に用いられることを特徴とする。
[1] The pharmaceutical composition according to the first aspect of the present invention has the following general formula (1) [wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently a hydrogen atom, -Z 1 -O-C(=O)-R 21 , or -Z 1 -S-C(= O)-R 21 ; the Z 1 is -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -C 4 H 6 -; one or more hydrogen atoms in Z 1 may be substituted with a substituent; R 21 is an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aryl group which may have a substituent; : A plurality of Z 1 and R 21 in one molecule may be the same group or different groups; however, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen atoms]
It is characterized in that it contains a compound represented by the following, or a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient, and is used for the treatment of hyperphosphatemia.
[2] 前記[1]の医薬用組成物は、前記R21が、置換基を有していてもよい炭素数1~4のアルキル基であることが好ましい。
[3] 前記[1]又は[2]の医薬用組成物は、前記R21が、n-プロピル基又はエチル基であることが好ましい。
[4] 前記[1]又は[2]の医薬用組成物は、前記R21が、置換基を有している炭素数1~6のアルキル基、又は、置換基を有しているアリール基であり、
前記置換基が、ハロゲン、炭素数1~4のアルキル基、アミノ基、ニトロ基、フェニル基、ヒドロキシ基、チオール基、炭素数1~4のアシル基、及びアリル基からなる群から選択される1種以上の基であることが好ましい。
[5] 前記[1]~[4]のいずれかの医薬用組成物は、前記Z1中の1又は複数の水素原子が、ハロゲン、炭素数1~4のアルキル基、アミノ基、ニトロ基、フェニル基、ヒドロキシ基、チオール基、炭素数1~4のアシル基、及びアリル基からなる群から選択される1種以上の基で置換されていることが好ましい。
[6] 前記[1]~[5]のいずれかの医薬用組成物は、前記R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12のうちの6個以上が水素原子ではないことが好ましい。
[7] 前記[6]の医薬用組成物は、前記R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の全てが水素原子ではないことが好ましい。
[8] 前記[1]~[7]のいずれかの医薬用組成物は、前記一般式(1)で表される化合物が、体内で加水分解されて、前記R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の一部又は全てが水素原子になることが好ましい。
[9] 前記[1]~[8]のいずれかの医薬用組成物は、血中無機リン値を低下させる作用を有することが好ましい。
[10] 前記[1]~[9]のいずれかの医薬用組成物は、石灰化を抑制する作用を有することが好ましい。
[11] 前記[1]~[10]のいずれかの医薬用組成物は、経口投与されることが好ましい。
[2] In the pharmaceutical composition of [1] above, R 21 is preferably an alkyl group having 1 to 4 carbon atoms which may have a substituent.
[3] In the pharmaceutical composition of [1] or [2] above, R 21 is preferably an n-propyl group or an ethyl group.
[4] In the pharmaceutical composition of [1] or [2] above, R 21 is an alkyl group having 1 to 6 carbon atoms having a substituent, or an aryl group having a substituent. and
The substituent is selected from the group consisting of halogen, an alkyl group having 1 to 4 carbon atoms, an amino group, a nitro group, a phenyl group, a hydroxy group, a thiol group, an acyl group having 1 to 4 carbon atoms, and an allyl group. Preferably, it is one or more groups.
[5] The pharmaceutical composition according to any one of [1] to [4] above, wherein one or more hydrogen atoms in Z 1 is a halogen, an alkyl group having 1 to 4 carbon atoms, an amino group, or a nitro group. , a phenyl group, a hydroxy group, a thiol group, an acyl group having 1 to 4 carbon atoms, and an allyl group.
[6] The pharmaceutical composition according to any one of [1] to [5] above includes the above R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R Preferably, six or more of 10 , R 11 , and R 12 are not hydrogen atoms.
[7] The pharmaceutical composition of [6] above comprises the above R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R Preferably, all 12 are not hydrogen atoms.
[8] In the pharmaceutical composition according to any one of [1] to [7], the compound represented by the general formula (1) is hydrolyzed in the body to form the R 1 , R 2 , and R 3 . , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are preferably partially or entirely hydrogen atoms.
[9] The pharmaceutical composition according to any one of [1] to [8] above preferably has an effect of lowering blood inorganic phosphorus levels.
[10] The pharmaceutical composition according to any one of [1] to [9] above preferably has an effect of suppressing calcification.
[11] The pharmaceutical composition according to any one of [1] to [10] above is preferably administered orally.
本発明に係る医薬用組成物は、血中の無機リン濃度自体を直接低下させることができ、さらに、経口投与によっても十分な治療効果が期待できることから、高リン血症の治療用として好適である。 The pharmaceutical composition according to the present invention can directly reduce the inorganic phosphorus concentration itself in the blood, and can also be expected to have a sufficient therapeutic effect even when administered orally, so it is suitable for the treatment of hyperphosphatemia. be.
本発明に係る医薬用組成物は、IP6のリン酸基の少なくとも一部がエステル化又はチオエステル化によって保護されたフィチン酸誘導体を有効成分とし、高リン血症の治療に用いられることを特徴とする。当該フィチン酸誘導体は、IP6の細胞膜透過性を改善したプロドラッグである。なお、本発明及び本願明細書において、「プロドラッグ」とは、生体内投与後に代謝されることによって、生物学的、医薬的、又は治療的に活性な型に転換される化合物を意味する。 The pharmaceutical composition according to the present invention is characterized in that it contains as an active ingredient a phytic acid derivative in which at least a part of the phosphate group of IP6 is protected by esterification or thioesterification, and is used for the treatment of hyperphosphatemia. do. The phytic acid derivative is a prodrug with improved cell membrane permeability of IP6. In the present invention and the present specification, the term "prodrug" refers to a compound that is converted into a biologically, pharmaceutically, or therapeutically active form by being metabolized after in vivo administration.
具体的には、本発明に係る医薬用組成物の有効成分とするフィチン酸エステル誘導体は、下記一般式(1)で表される化合物である。以降において、一般式(1)で表される化合物を、「Pro-IP6」と呼称する場合がある。 Specifically, the phytic acid ester derivative used as the active ingredient of the pharmaceutical composition according to the present invention is a compound represented by the following general formula (1). Hereinafter, the compound represented by general formula (1) may be referred to as "Pro-IP6".
一般式(1)中、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12は、それぞれ独立して、水素原子、-Z1-O-C(=O)-R21、又は、-Z1-S-C(=O)-R21である。ただし、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の全てが水素原子である化合物、すなわちIP6は、Pro-IP6からは除かれる。 In general formula (1), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently, It is a hydrogen atom, -Z 1 -O-C(=O)-R 21 , or -Z 1 -S-C(=O)-R 21 . However, compounds in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen atoms, that is, IP6 , is excluded from Pro-IP6.
Pro-IP6としては、好ましくは、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12のうち、2個以上、3個以上、4個以上、5個以上、6個以上、7個以上、8個以上、9個以上、10個以上、11個以上が水素原子ではない。「水素原子ではない」とは、-Z1-O-C(=O)-R21、又は、-Z1-S-C(=O)-R21であること、すなわち、エステル化又はチオエステル化されていることを意味する。本発明に係る医薬用組成物野有効成分のPro-IP6としては、一般式(1)のうち、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12のうちの6個以上が水素原子ではない化合物が好ましく、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の全てが水素原子ではない化合物がより好ましい。 Pro-IP6 is preferably two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 In the above, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more are not hydrogen atoms. "Not a hydrogen atom" means -Z 1 -OC(=O)-R 21 or -Z 1 -S-C(=O)-R 21 , that is, esterification or thioester It means that it is converted into The active ingredient Pro-IP6 of the pharmaceutical composition according to the present invention includes R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A compound in which 6 or more of R 9 , R 10 , R 11 , and R 12 are not hydrogen atoms is preferred, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all not hydrogen atoms.
一般式(1)中、R21は、置換基を有していてもよい炭素数1~6のアルキル基(C1-6アルキル基)、又は、置換基を有していてもよいアリール基である。一分子中に複数あるR21は、互いに同種の基であってもよく、異種の基であってもよい In the general formula (1), R 21 is an alkyl group having 1 to 6 carbon atoms (C 1-6 alkyl group) which may have a substituent, or an aryl group which may have a substituent. It is. A plurality of R21s in one molecule may be the same group or different groups.
R21が置換基を有していてもよいC1-6アルキル基である場合、当該C1-6アルキル基としては、直鎖であってもよく、分岐鎖であってもよい。具体的には、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、n-ペンチル基、イソペンチル基、ネオペンチル基、tert-ペンチル基、n-ヘキシル基等が挙げられる。 When R 21 is a C 1-6 alkyl group which may have a substituent, the C 1-6 alkyl group may be linear or branched. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert- Examples include pentyl group and n-hexyl group.
置換基を有しているC1-6アルキル基は、C1-6アルキル基の炭素原子に結合している水素原子の1又は複数個、好ましくは1~3個が、他の官能基に置換されている基である。2個以上の置換基を有する場合、置換基同士は互いに同種であってもよく、異種であってよい。当該置換基としては、特に限定されず、例えば、ハロゲン原子、炭素数1~4のアルキル基(C1-4アルキル基)、アミノ基、ニトロ基、ヒドロキシ基、チオール基、炭素数1~4のアシル基(C1-4アシル基)、アリル基等が挙げられる。また、当該置換基は、フェニル基のような大きな置換基であってもよい。R21としては、C1-6アルキル基が有している置換基は、ハロゲン原子、C1-4アルキル基、アミノ基、及びニトロ基からなる群より選択される1種以上が好ましい。 A C 1-6 alkyl group having a substituent has one or more hydrogen atoms, preferably 1 to 3 hydrogen atoms bonded to a carbon atom of the C 1-6 alkyl group, bonded to another functional group. It is a substituted group. When having two or more substituents, the substituents may be the same or different. The substituent is not particularly limited, and includes, for example, a halogen atom, an alkyl group having 1 to 4 carbon atoms (C 1-4 alkyl group), an amino group, a nitro group, a hydroxy group, a thiol group, and a thiol group having 1 to 4 carbon atoms. acyl group (C 1-4 acyl group), allyl group, etc. Further, the substituent may be a large substituent such as a phenyl group. As R 21 , the substituent that the C 1-6 alkyl group has is preferably one or more selected from the group consisting of a halogen atom, a C 1-4 alkyl group, an amino group, and a nitro group.
R21が置換基を有していてもよいアリール基である場合、当該アリールル基としては、フェニル基、ナフチル基、アントリル基、9-フルオレニル基等が挙げられ、フェニル基が特に好ましい。置換基を有しているアリール基は、アリール基の炭素原子に結合している水素原子の1又は複数個、好ましくは1~3個が、他の官能基に置換されている基である。2個以上の置換基を有する場合、置換基同士は互いに同種であってもよく、異種であってよい。当該置換基としては、特に限定されず、例えば、ハロゲン原子、C1-4アルキル基、アミノ基、ニトロ基、ヒドロキシ基、チオール基、C1-4アシル基、アリル基等が挙げられる。また、当該置換基は、フェニル基のような大きな置換基であってもよい。R21としては、アリール基が有している置換基は、ハロゲン原子、C1-4アルキル基、アミノ基、及びニトロ基からなる群より選択される1種以上が好ましい。 When R 21 is an aryl group which may have a substituent, examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, a 9-fluorenyl group, and a phenyl group is particularly preferred. An aryl group having a substituent is a group in which one or more, preferably one to three, hydrogen atoms bonded to a carbon atom of the aryl group are substituted with another functional group. When having two or more substituents, the substituents may be the same or different. The substituent is not particularly limited, and includes, for example, a halogen atom, a C 1-4 alkyl group, an amino group, a nitro group, a hydroxy group, a thiol group, a C 1-4 acyl group, an allyl group, and the like. Further, the substituent may be a large substituent such as a phenyl group. As R 21 , the substituent that the aryl group has is preferably one or more selected from the group consisting of a halogen atom, a C 1-4 alkyl group, an amino group, and a nitro group.
C1-6アルキル基及びアリール基が有していてもよい置換基のうち、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、又はヨウ素原子が挙げられる。
アミノ基は、アンモニア、第一級アミン、又は第二級アミンから水素原子を除いた1価の置換基の総称である。
チオール基は、水素化された硫黄を末端に持つ置換基である。当該チオール基としては、メタンチオール基、エタンチオール基、チオフェノール基を含む。
Among the substituents that the C 1-6 alkyl group and the aryl group may have, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The amino group is a general term for a monovalent substituent obtained by removing a hydrogen atom from ammonia, a primary amine, or a secondary amine.
A thiol group is a hydrogenated sulfur-terminated substituent. The thiol group includes a methanethiol group, an ethanethiol group, and a thiophenol group.
C1-4アルキル基としては、直鎖であってもよく、分岐鎖であってもよい。C1-4アルキル基の例としては、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基が挙げられる。 The C 1-4 alkyl group may be linear or branched. Examples of the C 1-4 alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group.
アシル基は、オキソ酸からヒドロキシル基を取り除いた形の置換基である。C1-4アシル基としては、アルキル基部分が、直鎖であってもよく、分岐鎖であってもよい。C1-4アシル基の例としては、ホルミル基、アセチル基、プロピオニル基、ブタノイル基が挙げられる。 An acyl group is a substituent obtained by removing the hydroxyl group from an oxoacid. As the C 1-4 acyl group, the alkyl group portion may be linear or branched. Examples of the C 1-4 acyl group include formyl group, acetyl group, propionyl group, and butanoyl group.
Pro-IP6としては、一分子中にあるR21の少なくとも一部が、置換基を有していてもよい炭素数1~4のアルキル基(C1-4アルキル基)が好ましく、一分子中にあるR21の全部が置換基を有していてもよいC1-4アルキル基がより好ましい。当該置換基を有していてもよいC1-4アルキル基としては、未置換のC1-4アルキル基が好ましく、未置換の直鎖のC1-4アルキル基がより好ましく、未置換のエチル基又はn-プロピル基がさらに好ましく、未置換のn-プロピル基が特に好ましい。 As for Pro-IP6, at least a part of R 21 in one molecule is preferably an alkyl group having 1 to 4 carbon atoms (C 1-4 alkyl group) which may have a substituent; More preferred is a C 1-4 alkyl group in which all of R 21 in the formula may have a substituent. The C 1-4 alkyl group which may have a substituent is preferably an unsubstituted C 1-4 alkyl group, more preferably an unsubstituted linear C 1-4 alkyl group, and an unsubstituted C 1-4 alkyl group is more preferable. Ethyl group or n-propyl group is more preferred, and unsubstituted n-propyl group is particularly preferred.
一般式(1)中、Z1は、-CH2-、-CH2-CH2-、又は、-CH2-C4H6-である。本発明に係る医薬用組成物の有効成分としては、Z1が置換基を有していない-CH2-であるPro-IP6が好ましい。細胞内で得られるPro-IP6の加水分解物の構造がIP6により類似しているためである。一分子中に複数あるZ1は、互いに同種の基であってもよく、異種の基であってもよい In general formula (1), Z 1 is -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -C 4 H 6 -. As the active ingredient of the pharmaceutical composition according to the present invention, Pro-IP6 in which Z 1 is -CH 2 - with no substituent is preferred. This is because the structure of the hydrolyzate of Pro-IP6 obtained within cells is more similar to IP6. A plurality of Z 1 's in one molecule may be the same group or different groups.
Z1中の1個又は複数個の水素原子は、置換基で置換されていてもよい。置換基の数及び種類は特に限定されない。Z1中の複数個の水素原子が置換基で置換されている場合、当該置換基は、同種の置換基であってもよく、異なる置換基で置換されていてもよい。当該置換基としては、特に限定されず、例えば、ハロゲン原子、C1-4アルキル基、アミノ基、ニトロ基、フェニル基、ヒドロキシ基、チオール基、C1-4アシル基、アリル基等が挙げられる。また、当該置換基は、フェニル基のような大きな置換基であってもよい。当該置換基のハロゲン原子、C1-4アルキル基、アミノ基、チオール基、C1-4アシル基としては、R21のC1-6アルキル基及びアリール基が有していてもよい置換基と同様のものを用いることができる。 One or more hydrogen atoms in Z 1 may be substituted with a substituent. The number and type of substituents are not particularly limited. When a plurality of hydrogen atoms in Z 1 are substituted with substituents, the substituents may be of the same type or may be substituted with different substituents. The substituent is not particularly limited, and includes, for example, a halogen atom, a C 1-4 alkyl group, an amino group, a nitro group, a phenyl group, a hydroxy group, a thiol group, a C 1-4 acyl group, an allyl group, etc. It will be done. Further, the substituent may be a large substituent such as a phenyl group. The halogen atom, C 1-4 alkyl group, amino group, thiol group, and C 1-4 acyl group of the substituent include substituents that the C 1-6 alkyl group and aryl group of R 21 may have. Something similar to can be used.
細胞内に取り込まれたPro-IP6は、細胞内の酵素によって、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12のうちの水素原子ではない基の少なくとも一部が加水分解される。R1等が-Z1-O-C(=O)-R21の場合、加水分解によって当該基は-Z1-OHとなり、カルボン酸であるR21-COOHが放出される。R1等が-Z1-S-C(=O)-R21の場合、加水分解によって当該基は-Z1-SHとなり、カルボン酸であるR21-COOHが放出される。 Pro-IP6 taken into cells is converted into R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , At least a portion of the groups that are not hydrogen atoms among R 12 and R 12 are hydrolyzed. When R 1 etc. is -Z 1 -OC(=O)-R 21 , the group becomes -Z 1 -OH by hydrolysis, and R 21 -COOH, which is a carboxylic acid, is released. When R 1 etc. is -Z 1 -S-C(=O)-R 21 , the group becomes -Z 1 -SH by hydrolysis, and R 21 -COOH, which is a carboxylic acid, is released.
Pro-IP6の加水分解物のうち、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12のうちの水素原子ではない基の全てが加水分解された化合物(完全加水分解Pro-IP6)は、IP6中のリン原子と直接結合していたヒドロキシ基を、-O-Z1-を介して結合させた構造、又は当該構造をさらにチオール基に変換した構造からなり、IP6と近似した構造を有しているIP6アナログである。細胞内に取り込まれたPro-IP6後に加水分解物により生じた完全加水分解Pro-IP6(IP6アナログ)は、IP6と同様にSLC20A2-XPR1リンクに作用する。つまり、細胞内に取り込まれたPro-IP6によって細胞内のIP6アナログ濃度が上昇する結果、IP6自体の濃度が上昇した場合と同様に、SLC20A2-XPR1リンクに作用して細胞内からのリン酸の排出が抑えられ、血中無機リン値が低下する。これは主に、細胞内のIP6/IP7比が増加したことによるXPR1の機能の抑制によるものと推察される。また、細胞内に取り込まれたPro-IP6の一部のエステル又はチオエステルが加水分解された分解物(部分分解Pro-IP6)は、IP6Kに対する阻害作用も有しており、当該作用も血中無機リン量の低減に寄与する。このように、Pro-IP6は、細胞からのリン酸の排出を抑えることによって血中の無機リン値自体を低減させることができるため、Pro-IP6を有効成分とする医薬用組成物は、高リン血症の治療又は予防に有効である。 Among the hydrolysates of Pro-IP6, hydrogen among R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 A compound in which all non-atomic groups have been hydrolyzed (completely hydrolyzed Pro-IP6) has a structure in which the hydroxy group that was directly bonded to the phosphorus atom in IP6 is bonded via -O-Z 1 -. , or a structure obtained by further converting this structure into a thiol group, and is an IP6 analog having a structure similar to IP6. Completely hydrolyzed Pro-IP6 (IP6 analogue) produced by a hydrolyzate after Pro-IP6 is taken up into cells acts on the SLC20A2-XPR1 link in the same way as IP6. In other words, the intracellular IP6 analog concentration increases due to Pro-IP6 taken into the cell, and as a result, phosphoric acid is released from within the cell by acting on the SLC20A2-XPR1 link, similar to when the concentration of IP6 itself increases. Excretion is suppressed and blood inorganic phosphorus levels are reduced. This is presumed to be mainly due to suppression of XPR1 function due to an increase in the intracellular IP6/IP7 ratio. In addition, the hydrolyzed product (partially degraded Pro-IP6) of a part of the ester or thioester of Pro-IP6 taken into cells also has an inhibitory effect on IP6K, and this effect also has an inhibitory effect on blood inorganic substances. Contributes to reducing the amount of phosphorus. In this way, Pro-IP6 can reduce the inorganic phosphorus level itself in the blood by suppressing the excretion of phosphate from cells, so a pharmaceutical composition containing Pro-IP6 as an active ingredient has a high It is effective in treating or preventing phosphatemia.
また、R21がn-プロピル基の場合には、Pro-IP6の加水分解により酪酸が放出され、R21がエチル基の場合には、Pro-IP6の加水分解によりプロピオン酸が放出される。酪酸には、リン酸カルシウムによるIL-6/P-ERKシグナルの活性化を抑える作用があり、また、酪酸とプロピオン酸は、リン酸カルシウムを可溶化する作用がある(非特許文献6)。これらのカルボン酸がいずれも高リン血症による石灰化を抑制する作用があることから、本発明に係る医薬用組成物の有効成分であるPro-IP6としては、R21の少なくとも一部がn-プロピル基又はエチル基である化合物が好ましく、R21の全部がn-プロピル基又はエチル基である化合物がより好ましい。なかでも、リン酸カルシウムはIL-6/P-ERKシグナルを活性化し炎症を引き起こすが、酪酸は、IL-6/P-ERKシグナルの活性化抑制による炎症抑制作用も期待できる点から、R21の全部がn-プロピル基である化合物がさらに好ましい。加水分解によって酪酸やプロピオン酸を放出するPro-IP6を有効成分とする医薬用組成物は、無機リン値を下げる作用に加えて、石灰化を抑える作用も有しているため、高リン血症の治療又は予防に極めて有効である。 Furthermore, when R 21 is an n-propyl group, butyric acid is released by hydrolysis of Pro-IP6, and when R 21 is an ethyl group, propionic acid is released by hydrolysis of Pro-IP6. Butyric acid has the effect of suppressing the activation of IL-6/P-ERK signals by calcium phosphate, and butyric acid and propionic acid have the effect of solubilizing calcium phosphate (Non-Patent Document 6). Since all of these carboxylic acids have the effect of suppressing calcification caused by hyperphosphatemia, Pro-IP6, which is the active ingredient of the pharmaceutical composition according to the present invention, has at least a portion of R 21 -Propyl or ethyl groups are preferred, and compounds in which all of R 21 are n-propyl or ethyl groups are more preferred. Among them, calcium phosphate activates IL-6/P-ERK signals and causes inflammation, but butyric acid is expected to have an anti-inflammatory effect by suppressing the activation of IL-6/P-ERK signals. More preferred are compounds in which is an n-propyl group. Pharmaceutical compositions containing Pro-IP6 as an active ingredient, which releases butyric acid and propionic acid upon hydrolysis, have the effect of lowering inorganic phosphorus levels as well as suppressing calcification, thus preventing hyperphosphatemia. It is extremely effective for the treatment or prevention of.
Pro-IP6としては、一般式(1)で表される化合物のうち、一分子中にあるZ1の全部が置換基を有していない-CH2-であり、かつ一分子中にあるR21の少なくとも一部が、置換基を有していてもよい炭素数1~4のアルキル基(C1-4アルキル基)である化合物が好ましく、一分子中にあるZ1の全部が置換基を有していない-CH2-であり、かつ一分子中にあるR21の全部が置換基を有していてもよいC1-4アルキル基である化合物がより好ましく、一分子中にあるZ1の全部が置換基を有していない-CH2-であり、かつ一分子中にあるR21の全部が未置換のC1-4アルキル基である化合物さらに好ましく、一分子中にあるZ1の全部が置換基を有していない-CH2-であり、かつ一分子中にあるR21の全部が直鎖の未置換のC1-4アルキル基である化合物よりさらに好ましく、一分子中にあるZ1の全部が置換基を有していない-CH2-であり、かつ一分子中にあるR21の全部がn-プロピル基又はエチル基である化合物がよりさらに好ましく、一分子中にあるZ1の全部が置換基を有していない-CH2-であり、かつ一分子中にあるR21の全部がn-プロピル基又である化合物が特に好ましい。 Pro-IP6 is a compound represented by general formula (1) in which all of Z 1 in one molecule are -CH 2 - with no substituents, and R in one molecule is A compound in which at least a part of 21 is an alkyl group having 1 to 4 carbon atoms (C 1-4 alkyl group) which may have a substituent is preferable, and all of Z 1 in one molecule are a substituent. It is more preferable to use a compound in which R 21 in one molecule is a C 1-4 alkyl group which may have a substituent. Compounds in which all of Z 1 are -CH 2 - with no substituents, and all of R 21 in one molecule are unsubstituted C 1-4 alkyl groups are more preferred; It is more preferable than a compound in which all of Z 1 is -CH 2 - having no substituents, and all of R 21 in one molecule are linear unsubstituted C 1-4 alkyl groups. A compound in which all of Z 1 in the molecule is -CH 2 - with no substituent, and all of R 21 in one molecule is an n-propyl group or an ethyl group is even more preferable. Particularly preferred are compounds in which all Z 1 's in the molecule are -CH 2 - with no substituents, and all R 21 's in one molecule are n-propyl groups.
一般式(1)で表されるPro-IP6の合成方法は特に限定されない。リン酸基をエステル化するための公知の方法を用いることが可能である。例えば、まずカルボン酸からカルボン酸ハロゲンアルキルエステルを合成する。これを、トリエチルアミン等の強塩基性の置換基で活性化されているIP6の塩基性塩に反応させ、IP6のエステル誘導体を得ることができる。 The method for synthesizing Pro-IP6 represented by general formula (1) is not particularly limited. It is possible to use known methods for esterifying phosphate groups. For example, first, a carboxylic acid halogen alkyl ester is synthesized from a carboxylic acid. This can be reacted with a basic salt of IP6 activated with a strong basic substituent such as triethylamine to obtain an ester derivative of IP6.
本発明に係る医薬用組成物の有効成分としては、Pro-IP6の薬理学的に許容される塩であってもよい。Pro-IP6の薬理学的に許容される塩としては、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12のうちの水素原子である部分に対するナトリウム塩やカリウム塩等のアルカリ塩が挙げられる。 The active ingredient of the pharmaceutical composition according to the present invention may be a pharmacologically acceptable salt of Pro-IP6. Pharmaceutically acceptable salts of Pro-IP6 include R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R Examples include alkali salts such as sodium salts and potassium salts for the portion of 12 that is a hydrogen atom.
本発明に係る医薬用組成物の有効成分としては、Pro-IP6の溶媒和物又はPro-IP6の薬理学的に許容される塩の溶媒和物であってもよい。当該溶媒和物を形成する溶媒としては、水、エタノール等が挙げられる。 The active ingredient of the pharmaceutical composition according to the present invention may be a solvate of Pro-IP6 or a solvate of a pharmacologically acceptable salt of Pro-IP6. Examples of the solvent that forms the solvate include water, ethanol, and the like.
本発明に係る医薬用組成物は、Pro-IP6のみからなるものであってもよく、その他の成分を含むものであってもよい。本発明に係る医薬用組成物としては、Pro-IP6を薬理学的に許容可能な担体と組み合わせて、製剤上の常套手段により様々な剤型に製剤化することができる。「薬理学的に許容可能な担体」は、製剤の他の成分と適合し、被験者に有害ではない、任意の担体、希釈剤又は賦形剤を意味する。本願明細書の開示に基づき、Pro-IP6を含む医薬組成物を処方することは、本技術分野の範囲内である。例えば、医薬品の分野の標準的技法に従って、Pro-IP6を含む医薬組成物を処方することが可能である。例えば、Alphonso Gennaro,ed.,Remington’s Pharmaceutical Sciences,18th Ed.,(1990)Mack Publishing Co.,Easton,Paを参照。 The pharmaceutical composition according to the present invention may consist only of Pro-IP6 or may contain other components. The pharmaceutical composition according to the present invention can be formulated into various dosage forms using conventional pharmaceutical methods by combining Pro-IP6 with a pharmacologically acceptable carrier. "Pharmacologically acceptable carrier" means any carrier, diluent, or excipient that is compatible with the other ingredients of the formulation and not deleterious to the subject. Based on the disclosure herein, it is within the skill of the art to formulate pharmaceutical compositions containing Pro-IP6. For example, it is possible to formulate a pharmaceutical composition comprising Pro-IP6 according to standard techniques in the pharmaceutical field. See, for example, Alphonso Gennaro, ed. , Remington's Pharmaceutical Sciences, 18th Ed. , (1990) Mack Publishing Co. , Easton, Pa.
本発明に係る医薬用組成物は、所望により、さらに、安定化剤、酸化防止剤、及び保存料が添加されてもよい。適切な酸化防止剤は、例えば、亜硫酸、アスコルビン酸,クエン酸及びその塩、並びにナトリウムEDTAを含む。適切な保存料は、例えば、塩化ベンザルコニウム、メチル-又はプロピル-パラベン、及びクロルブタノールを含む。 The pharmaceutical composition according to the present invention may further contain a stabilizer, an antioxidant, and a preservative, if desired. Suitable antioxidants include, for example, sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include, for example, benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
本発明に係る医薬用組成物は、所望により、さらに、1又はそれ以上の他の有効成分を含んでもよい。「他の有効成分」は、Pro-IP6と同様に、血中無機リン値の低減や、石灰化の抑制のいずれかの活性を有する成分が好ましい。本発明に係る医薬用組成物は、これら以外の活性を有する成分であってもよい。 The pharmaceutical composition according to the present invention may further contain one or more other active ingredients, if desired. As with Pro-IP6, the "other active ingredients" are preferably ingredients that have the activity of reducing blood inorganic phosphorus levels or inhibiting calcification. The pharmaceutical composition according to the present invention may contain components having activities other than those described above.
本発明に係る医薬用組成物の投与経路は特に限定されない。例えば、錠剤、カプセル剤、顆粒剤、トローチ、ドリンク剤等に処方して経口投与してもよい。あるいは、パッチ剤等の経皮投与、腹腔内投与、静脈内点滴若しくは注射等による静脈内投与などの非経口投与を用いてもよい。その他、筋肉内注射等による筋肉内投与、経腸投与、局所投与等による投与も可能である。一態様において、本発明に係る医薬用組成物は、経口投与、経皮投与、腹腔内投与又は静脈内投与される。本発明に係る医薬用組成物の処方(製剤)の具体例を以下に示す。 The route of administration of the pharmaceutical composition according to the present invention is not particularly limited. For example, it may be formulated into tablets, capsules, granules, troches, drinks, etc. and administered orally. Alternatively, parenteral administration such as transdermal administration such as a patch, intraperitoneal administration, intravenous administration by intravenous drip or injection, etc. may be used. In addition, intramuscular administration such as intramuscular injection, enteral administration, local administration, etc. are also possible. In one aspect, the pharmaceutical composition according to the present invention is administered orally, transdermally, intraperitoneally, or intravenously. Specific examples of formulations of the pharmaceutical composition according to the present invention are shown below.
例えば、経口投与用の錠剤、散剤、顆粒剤、トローチ、カプセル剤等は、Pro-IP6を含む医薬組成物に、例えば賦形剤、崩壊剤、結合剤又は滑沢剤等の1つ以上の固形不活性成分を添加して圧縮成型し、次いで必要により、味のマスキング、腸溶性あるいは持続性の目的のためのコーティングを行うことにより製造することができる。 For example, tablets, powders, granules, troches, capsules, etc. for oral administration may be prepared by adding one or more excipients, disintegrants, binders or lubricants to the pharmaceutical composition containing Pro-IP6. They can be prepared by adding solid inert ingredients, compression molding, and then optionally coating for taste masking, enteric or long-lasting purposes.
注射剤は、例えば、Pro-IP6を含む医薬組成物を、例えば分散剤、保存剤、等張化剤等と共に水性注射剤として、あるいはオリーブ油、ゴマ油、綿実油、コーン油等の植物油、プロピレングリコール等に溶解、懸濁あるいは乳化して油性注射剤として成型することにより製造することができる。 Injections include, for example, a pharmaceutical composition containing Pro-IP6 as an aqueous injection together with a dispersant, a preservative, a tonicity agent, etc., or a vegetable oil such as olive oil, sesame oil, cottonseed oil, and corn oil, propylene glycol, etc. It can be manufactured by dissolving, suspending, or emulsifying the mixture and molding it into an oil-based injection.
外用剤は、例えば、Pro-IP6を含む医薬組成物を固状、半固状又は液状の組成物とすることにより製造される。例えば、上記固状の組成物は、該医薬組成物をそのまま、あるいは賦形剤、増粘剤などを添加、混合して粉状とすることにより製造される。上記液状の組成物は、注射剤の場合とほとんど同様で、油性あるいは水性懸濁剤とすることにより製造される。半固状の組成物は、水性又は油性のゲル剤、あるいは軟膏状のものがよい。また、これらの組成物は、いずれも緩衝剤、防腐剤などを含んでいてもよい。外用剤は、例えば、局所投与用のクリーム、ローション、ゲル、軟膏等が含まれる。 The external preparation is produced, for example, by preparing a pharmaceutical composition containing Pro-IP6 into a solid, semi-solid, or liquid composition. For example, the above-mentioned solid composition can be produced by powdering the pharmaceutical composition as it is or by adding and mixing excipients, thickeners, etc. The above-mentioned liquid composition is produced in almost the same way as an injection by forming it into an oil-based or aqueous suspension. The semi-solid composition is preferably in the form of an aqueous or oily gel or an ointment. Furthermore, all of these compositions may contain buffering agents, preservatives, and the like. External preparations include, for example, creams, lotions, gels, ointments, etc. for topical administration.
座剤は、例えばPro-IP6を含む医薬組成物を油性又は水性の固状、半固状あるいは液状の組成物とすることにより製造される。このような組成物に用いる油性基剤としては、例えば、高級脂肪酸のグリセリド(例えば、カカオ脂、ウイテプゾル類等)、中級脂肪酸(例えば、ミグリオール類等)、あるいは植物油(例えば、ゴマ油、大豆油、綿実油等)等が挙げられる。水性ゲル基剤としては、例えば天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体等が挙げられる。 Suppositories are produced, for example, by preparing a pharmaceutical composition containing Pro-IP6 into an oil-based or aqueous solid, semi-solid, or liquid composition. Examples of oily bases used in such compositions include glycerides of higher fatty acids (e.g., cocoa butter, Huitepsols, etc.), intermediate fatty acids (e.g., miglyols, etc.), or vegetable oils (e.g., sesame oil, soybean oil, etc.). cottonseed oil, etc.). Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
本発明に係る医薬用組成物としては、経口投与される剤型であることが好ましい。経口投与されたPro-IP6の一部は、腸内細菌によって加水分解される。加水分解により得られた完全加水分解Pro-IP6は、血液中に取り込まれ、石灰化を抑制する(非特許文献3)。また、Pro-IP6の加水分解により放出されるカルボン酸が酪酸やプロピオン酸の場合には、これらのカルボン酸がリン酸カルシウムを可溶化することにより、石灰化を抑制できる(非特許文献3)。一方で、腸で加水分解されずに残ったPro-IP6は、細胞内に取り込まれ、部分分解Pro-IP6となり、IP6Kを阻害し、血中無機リン値を低下させる。さらに、Pro-IP6の加水分解により放出されるカルボン酸が酪酸やプロピオン酸の場合には、これらのカルボン酸がIL-6/P-ERKシグナルの活性化を抑え、リン酸カルシウムによる炎症を抑制する。このように、経口投与の場合には、血中無機リン値の低減効果だけではなく、石灰化の抑制効果や石灰化による炎症の抑制効果も得られる。このように、血中無機リン値と石灰化の両方を抑制する薬効成分は、本願発明においてはじめて見いだされた知見である。 The pharmaceutical composition according to the present invention is preferably in a dosage form that can be administered orally. A portion of orally administered Pro-IP6 is hydrolyzed by intestinal bacteria. Completely hydrolyzed Pro-IP6 obtained by hydrolysis is taken into the blood and suppresses calcification (Non-Patent Document 3). Furthermore, when the carboxylic acid released by hydrolysis of Pro-IP6 is butyric acid or propionic acid, calcification can be suppressed by solubilizing calcium phosphate with these carboxylic acids (Non-Patent Document 3). On the other hand, Pro-IP6 that remains unhydrolyzed in the intestines is taken into cells and becomes partially degraded Pro-IP6, which inhibits IP6K and lowers blood inorganic phosphorus levels. Furthermore, when the carboxylic acid released by hydrolysis of Pro-IP6 is butyric acid or propionic acid, these carboxylic acids suppress activation of IL-6/P-ERK signals and suppress inflammation caused by calcium phosphate. Thus, in the case of oral administration, not only the effect of reducing blood inorganic phosphorus levels but also the effect of suppressing calcification and inflammation caused by calcification can be obtained. As described above, the medicinal ingredient that suppresses both blood inorganic phosphorus levels and calcification is a knowledge discovered for the first time in the present invention.
本発明に係る医薬用組成物の投与量及び投与期間は、投与対象のサイズ、質量、年齢及び性別、治療される疾患の性質及び段階、疾患の攻撃性、投与経路、並びに放射線の特定の毒性を含む個々の患者の特定の状況によって決定される。投与量及び投与期間は、また、既知の試験プロトコルを用いて実験的に、又は生体内若しくは生体外試験データからの外挿法によって決定されうる。本願明細書に記載する濃度範囲は、例示的な目的のみであり、請求される組成物の範囲または実施化を制限するものではない。 The dosage and administration period of the pharmaceutical composition according to the present invention are determined depending on the size, mass, age, and sex of the subject to be administered, the nature and stage of the disease to be treated, the aggressiveness of the disease, the route of administration, and the specific toxicity of radiation. determined by the specific circumstances of the individual patient, including: Dosages and durations of administration can also be determined experimentally using known test protocols or by extrapolation from in vivo or in vitro test data. The concentration ranges set forth herein are for exemplary purposes only and are not intended to limit the scope or implementation of the claimed compositions.
例えば、Pro-IP6を含む医薬組成物中の投与量は、有効成分であるPro-IP6の量で、好ましくは0.01~2000mg/kg/日、より好ましくは0.05~1000mg/kg/日、さらに好ましくは1.0~200mg/kg/日である。本発明に係る医薬用組成物は、1日1回で投与されてもよく、又は同時に若しくは時間間隔を置いて投与される何回かの低用量に分割されてもよい。 For example, the dosage in a pharmaceutical composition containing Pro-IP6 is the amount of Pro-IP6 as an active ingredient, preferably 0.01 to 2000 mg/kg/day, more preferably 0.05 to 1000 mg/kg/day. per day, more preferably 1.0 to 200 mg/kg/day. The pharmaceutical composition according to the invention may be administered once a day or may be divided into a number of lower doses administered simultaneously or at intervals of time.
本発明に係る医薬用組成物が投与される動物は、特に限定されるものではなく、ヒトであってもよく、ヒト以外の動物であってもよい。非ヒト動物としては、ウシ、ブタ、ウマ、ヒツジ、ヤギ、サル、イヌ、ネコ、ウサギ、マウス、ラット、ハムスター、モルモット等の哺乳動物等が挙げられる。 The animal to which the pharmaceutical composition according to the present invention is administered is not particularly limited, and may be a human or a non-human animal. Examples of non-human animals include mammals such as cows, pigs, horses, sheep, goats, monkeys, dogs, cats, rabbits, mice, rats, hamsters, and guinea pigs.
次に実施例を示して本発明をさらに詳細に説明するが、本発明は以下の実施例に限定されるものではない。 EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples.
[実施例1]
一般式(1)のうち、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の全てが-CH2-O-C(=O)-CH2-CH2-CH3である化合物(myo-イノシトール六リン酸ドデカキス(ブチリルオキシメチル)エステル)をマウスに投与し、血中無機リン値に対する影響を調べた。myo-イノシトール六リン酸ドデカキス(ブチリルオキシメチル)エステル(以降、「Pro-IP6酪酸エステル」)ということがある)は、特許文献1に記載されている方法で合成したものを用いた。
[Example 1]
In general formula (1), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all -CH 2 The compound -OC(=O)-CH 2 -CH 2 -CH 3 (myo-inositol hexaphosphate dodecakis (butyryloxymethyl) ester) was administered to mice, and the effect on blood inorganic phosphorus levels was investigated. Examined. Myo-inositol hexaphosphate dodecakis(butyryloxymethyl) ester (hereinafter sometimes referred to as "Pro-IP6 butyric acid ester") was synthesized by the method described in Patent Document 1.
C57/6Jマウス(4週齢、日本クレア社製)に対して、高脂肪食(製品名「High Fat Diet 32」、日本クレア社製)を8週間食餌することによって、高脂肪食餌誘発性糖尿病モデルマウスを作成した。なお、食餌及び飲料水は自由に与えた。モデルマウス作成後、Pro-IP6酪酸エステルを、1mL容シリンジ及び金属ゾンデを用いて、1日1回強制経口投与した。投与量は、Pro-IP6酪酸エステル(100mg/kg体重、300mg/kg体重)、メトホルミン(300mg/kg体重)とし、投与液量は5mL/kg体重とした。投与量は、直近の体重に基づいて個体別に算出した。Pro-IP6酪酸エステルは、オリーブ油に溶解させた溶液を投与液として用いた。当該投与液は、冷蔵庫(4℃、遮光)に保管して、7日に1度調製した。対照として、オリーブ油のみを投与した。各薬物を6週投与した後、麻酔をかけたマウスの心臓から300μLの血液を採取した。この血液を室温で30分間静置し、氷上でさらに30分間以上静置した。その後、当該血液を遠心分離処理して得られた上清を、-80℃で保存し、試料とした。試料中の血清パラメータの測定は、熊本大学生命資源研究・支援センターのマウスクリニックに依頼して解析した。 C57/6J mice (4 weeks old, manufactured by CLEA Japan) were fed a high-fat diet (product name "High Fat Diet 32", manufactured by CLEA Japan) for 8 weeks to induce high-fat diet-induced diabetes. Created a model mouse. In addition, food and drinking water were provided ad libitum. After creating model mice, Pro-IP6 butyrate was forcibly administered orally once a day using a 1 mL syringe and a metal probe. The dosage was Pro-IP6 butyrate (100 mg/kg body weight, 300 mg/kg body weight) and metformin (300 mg/kg body weight), and the volume of the administered liquid was 5 mL/kg body weight. The dose was calculated for each individual based on the most recent body weight. A solution of Pro-IP6 butyrate dissolved in olive oil was used as the administration solution. The administration solution was stored in a refrigerator (4° C., protected from light) and prepared once every 7 days. As a control, only olive oil was administered. After 6 weeks of administration of each drug, 300 μL of blood was collected from the heart of anesthetized mice. This blood was allowed to stand at room temperature for 30 minutes, and then on ice for an additional 30 minutes or more. Thereafter, the blood was centrifuged and the resulting supernatant was stored at -80°C and used as a sample. Measurement of serum parameters in the samples was performed at the Mouse Clinic of the Kumamoto University Life Resources Research and Support Center.
結果を図2に示す。図中、「Pro-IP6」は「Pro-IP6酪酸エステル」を投与した群の結果であり、「-」はオリーブ油投与群の結果である。また、図中、アスタリスクは、P<0.05を示す。 The results are shown in Figure 2. In the figure, "Pro-IP6" is the result of the group administered with "Pro-IP6 butyrate", and "-" is the result of the group administered with olive oil. Moreover, in the figure, an asterisk indicates P<0.05.
この結果、血中無機リン値(IP)は、オリーブ油投与群では7.04±0.69mg/dLであり、メトホルミン投与群では7.48±0.37mg/dLであったのに対して、Pro-IP6酪酸エステルを100mg/kg体重投与下群では8.88±0.07mg/dLであり、Pro-IP6酪酸エステルを300mg/kg体重投与下群では4.78±0.35mg/dLであった。これらの結果から、高脂肪食負荷マウスにおいては血液中の無機リン値が高くなるが、Pro-IP6の経口投与により、血中無機リン値を強力に低下させられることがわかった。 As a result, the blood inorganic phosphorus level (IP) was 7.04 ± 0.69 mg/dL in the olive oil administration group and 7.48 ± 0.37 mg/dL in the metformin administration group, whereas It was 8.88 ± 0.07 mg/dL in the Pro-IP6 butyrate ester administration group at 100 mg/kg body weight, and 4.78 ± 0.35 mg/dL in the Pro-IP6 butyrate ester administration group at 300 mg/kg body weight. there were. These results revealed that blood inorganic phosphorus levels are high in mice fed a high-fat diet, but oral administration of Pro-IP6 can strongly reduce blood inorganic phosphorus levels.
Claims (11)
で表される化合物、若しくはその薬理学的に許容される塩、又はそれらの溶媒和物を有効成分とし、高リン血症の治療に用いられることを特徴とする、医薬用組成物。 General formula (1) below
A pharmaceutical composition comprising a compound represented by the above, a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient, and is used for the treatment of hyperphosphatemia.
前記置換基が、ハロゲン、炭素数1~4のアルキル基、アミノ基、ニトロ基、フェニル基、ヒドロキシ基、チオール基、炭素数1~4のアシル基、及びアリル基からなる群から選択される1種以上の基である、請求項1又は2に記載の医薬用組成物。 R 21 is an alkyl group having 1 to 6 carbon atoms having a substituent, or an aryl group having a substituent,
The substituent is selected from the group consisting of halogen, an alkyl group having 1 to 4 carbon atoms, an amino group, a nitro group, a phenyl group, a hydroxy group, a thiol group, an acyl group having 1 to 4 carbon atoms, and an allyl group. Pharmaceutical composition according to claim 1 or 2, which is one or more groups.
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